Abstract
Stochastic fluctuations in gene expression (”noise”) are often
considered detrimental, but fluctuations can also be exploited for
benefit (e.g., dither). We show here that DNA base excision repair
amplifies transcriptional noise to facilitate cellular reprogramming.
Specifically, the DNA repair protein Apex1, which recognizes both
naturally occurring and unnatural base modifications, amplifies
expression noise while homeostatically maintaining mean expression
levels. This amplified expression noise originates from
shorter-duration, higher-intensity transcriptional bursts generated by
Apex1-mediated DNA supercoiling. The remodeling of DNA topology first
impedes and then accelerates transcription to maintain mean levels. This
mechanism, which we refer to as “discordant transcription through
repair” (”DiThR,” which is pronounced “dither”),
potentiates cellular reprogramming and differentiation. Our study
reveals a potential functional role for transcriptional fluctuations
mediated by DNA base modifications in embryonic development and disease.
